Pyrimidine nucleoside compound or its salt

Abstract

Provided is a pyrimidine nucleoside compound represented by the following formula (1): or a pharmaceutically acceptable salt thereof, wherein one of X and Y represents a cyano group, and the other represents a hydrogen atom; one of R 1 and R 2 represents a hydrogen atom, a carbonyl group having a C1-C6 alkyl group which has been mono-substituted by an amino group, or a group represented by (R 3 )(R 4 )(R 5 )Si—, and the other represents a group represented by (R 6 )(R 7 )(R 8 )Si—, or R 1 and R 2 together form a 6-membered cyclic group represented by —Si(R 9 )(R 10 )—; R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 each represent a C1-C10 linear or branched alkyl group which may have a substituent, a C3-C6 cycloalkyl group which may have a substituent, a C6-C14 aryl group which may have a substituent, or a C1-C6 alkyl group which has been substituted by one or two C6-C14 aryl groups and which may have a substituent; and R 9 and R 10 each represent a C1-C6 linear or branched alkyl group which may have a substituent. The pyrimidine nucleoside compound of formula (1) or a pharmaceutically acceptable salt thereof exhibits a potent antitumor effect and is therefore useful as a therapeutic agent for preventing or treating a tumor.

1. A pyrimidine nucleoside compound represented by the following formula (1): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein 
         one of X and Y represents a cyano group, and the other represents a hydrogen atom; 
         one of R 1  and R 2  represents a hydrogen atom, a carbonyl group having a C1-C6 alkyl group which has been mono-substituted by an amino group, or a group represented by (R 3 )(R 4 )(R 5 )Si—, and the other represents a group represented by (R 6 )(R 7 )(R 8 )Si—, or R 1  and R 2  together form a 6-membered cyclic group represented by —Si(R 9 )(R 10 )—; 
         R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  each represent a substituted or non-substituted C1-C10 linear or branched alkyl group, a substituted or non-substituted C3-C6 cycloalkyl group, a substituted or non-substituted C6-C14 aryl group, or a substituted C1-C6 alkyl group which has been substituted by one or two C6-C14 aryl groups, wherein the one or two C6-C14 aryl groups are optionally substituted by a substituent selected from the group consisting of a C1-C3 linear or branched alkyl group, a hydroxyl group, a C1-C6 linear or branched alkoxy group, an amino group, a halogen atom, a cyano group, and a nitro group; and 
         R 9  and R 10  each represent a substituted or non-substituted C1-C6 linear or branched alkyl group. 
       
     
     
       2. The pyrimidine nucleoside compound of formula (1) or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein
 one of X and Y represents a cyano group, and the other represents a hydrogen atom; 
 one of R 1  and R 2  represents a hydrogen atom, a carbonyl group having a C1-C6 alkyl group which has been mono-substituted by an amino group, or a group represented by (R 3 )(R 4 )(R 5 )Si—, and the other represents a group represented by (R 6 )(R 7 )(R 8 )Si—, or R 1  and R 2  together form a 6-membered cyclic group represented by —Si(R 9 )(R 10 )—; 
 R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 , which may be identical to or different from one another, individually represent a C1-C8 linear or branched alkyl group optionally substituted with a substituent selected from the group consisting of a C1-C6 linear or branched alkoxy group, a C3-C6 cycloalkyl group, a phenyl group, and a benzyl group. 
 
     
     
       3. The pyrimidine nucleoside compound of formula (1) or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein
 one of X and Y represents a cyano group, and the other represents a hydrogen atom; 
 R 1  represents a hydrogen atom, a valyl group, or a group represented by (R 3 )(R 4 )(R 5 )Si—; 
 R 2  represents a hydrogen atom or a group represented by (R 6 )(R 7 )(R 8 )Si—, with the proviso that when R 1  is a hydrogen atom or a valyl group, R 2  does not represent a hydrogen atom; and 
 R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 , which may be identical to or different from one another, each represent a C1-C8 linear or branched alkyl group or a C3-C6 cycloalkyl group. 
 
     
     
       4. The pyrimidine nucleoside compound of formula (1) or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein
 one of X and Y represents a cyano group, and the other represents a hydrogen atom; 
 R 1  represents a hydrogen atom, an L-valyl group, or a group represented by (R 3 )(R 4 )(R 5 )Si—; 
 R 2  represents a hydrogen atom or a group represented by (R 6 )(R 7 )(R 8 )Si—, with the proviso that when R 1  is a hydrogen atom or an L-valyl group, R 2  does not represent a hydrogen atom; and 
 any one of R 3 , R 4 , and R 5  and any one of R 6 , R 7 , and R 8 , which may be identical to or different from each other, individually represent a C3-C8 linear or branched alkyl group or a cyclopropyl group, and the other groups, which may be identical to or different from each other, each represent a C1-C4 linear or branched alkyl group. 
 
     
     
       5. The pyrimidine nucleoside compound of formula (1) or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein
 one of X and Y represents a cyano group, and the other represents a hydrogen atom; 
 R 1  represents a hydrogen atom, an L-valyl group, a triisopropylsilyl group, a diethylisopropylsilyl group, a dimethylthexylsilyl group, or a dimethyl-n-octylsilyl group; R 2  represents a hydrogen atom, a tert-butyldimethylsilyl group, a triisopropylsilyl group, a diethylisopropylsilyl group, a cyclopropyldiisopropylsilyl group, or a dimethylthexylsilyl group, with the proviso that when R 1  is a hydrogen atom or an L-valyl group, R 2  does not represent a hydrogen atom. 
 
     
     
       6. The pyrimidine nucleoside compound of formula (1) or a pharmaceutically acceptable salt thereof according to  claim 1 , which is selected from the group consisting of:
 5′-O-triisopropylsilyl-2′-cyano-2′-deoxy-1-β-D-arabinofuranosylcytosine; 
 5′-O-diethylisopropylsilyl-2′-cyano-2′-deoxy-1-β-D-arabinofuranosylcytosine; 
 5′-O-dimethylthexylsilyl-2′-cyano-2′-deoxy-1-β-D-arabinofuranosylcytosine; 
 5′-O-(dimethyl-n-octylsilyl)-2′-cyano-2′-deoxy-1-β-D-arabinofuranosylcytosine; 
 3′-O-dimethylthexylsilyl-2′-cyano-2′-deoxy-1-β-D-arabinofuranosylcytosine; 
 3′-O-diethylisopropylsilyl-2′-cyano-2′-deoxy-1-β-D-arabinofuranosylcytosine; 
 3′-O-(tert-butyldimethylsilyl)-2′-cyano-2′-deoxy-1-β-D-arabinofuranosylcytosine; 
 3′-O-triisopropylsilyl-2′-cyano-2′-deoxy-1-β-D-arabinofuranosylcytosine; 
 3′-O-dimethylthexylsilyl-5′-O-(L-valyl)-2′-cyano-2′-deoxy-1-β-D-arabinofuranosylcytosine; 
 5′-O-(L-valyl)-3′-O-(tert-butyldimethylsilyl)-2′-cyano-2′-deoxy-1-β-D-arabinofuranosylcytosine; and 
 3′-O-cyclopropyldiisopropylsilyl-2′-cyano-2′-deoxy-1-β-D-arabinofuranosylcytosine. 
 
     
     
       7. The pyrimidine nucleoside compound of formula (1) or a pharmaceutically acceptable salt thereof according to  claim 1 , wherein the substituent(s) bonded to R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9  or R 10  is selected from the group consisting of a C1-C3 linear or branched alkyl group, a hydroxyl group, a C1-C6 linear or branched alkoxy group, an amino group, a halogen atom, a cyano group, and a nitro group. 
     
     
       8. A pharmaceutical composition comprising: a therapeutically effective amount of a pyrimidine nucleoside compound of formula (1) or a pharmaceutically acceptable salt thereof as recited in any of  claims 1  to  6 ; and a pharmaceutically acceptable carrier. 
     
     
       9. A method for treating an intestinal tumor comprising administering to a subject in need thereof a therapeutically effective amount of a pyrimidine nucleoside compound of formula (1) or a pharmaceutically acceptable salt thereof as recited in any of  claims 1  to  6 .